Clinical and Radiographic Characteristics

ALK rearrangements occur in approximately 5% of patients with NSCLC. Although initially identified as EML4-ALK, fusions with a variety of other genes have been reported, all leading to dysregulated overexpression of ALK. Patients with ALK-positive tumors tend to be younger and more likely to be never or light smokers, with ALK rearrangements occurring in 12% of never-smokers compared with only 2% of former or current smokers. ALK rearrangements almost never co-occur with activating mutations in EGFR or KRAS. As compared with patients with EGFR -mutant NSCLC, patients with ALK-positive tumors are more likely to be men, and radiographically, are associated with larger-volume, multifocal thoracic lymphadenopathy.

Methods for Identifying Patients with Anaplastic Lymphoma Kinase–Positive Lung Cancers

ALK-positive tumors represent a subset of adenocarcinomas and may be more likely to exhibit certain histopathological features such as solid growth pattern and signet-ring cell cytomorphology or mucinous cribiform pattern ; however, these characteristics are neither sensitive nor specific for ALK rearrangements. Specific testing for the molecular patterns of ALK gene fusion or the resultant ALK protein overexpression is required for diagnosis of ALK-positive NSCLC.

During initial evaluation of crizotinib, the ALK break-apart test was used to identify ALK-positive patients. This test uses fluorescence in situ hybridization (FISH), capitalizes on disruption of the ALK gene, and was the first test to be US Food and Drug Administration (FDA) approved. Although the FISH test can identify many ALK rearrangements, routine next-generation sequencing (NGS) can identify ALK rearrangements not previously identified and those with complex fusion partners, thus identifying more patients that would be appropriate for ALK-directed therapy. Furthermore, routine NGS can identify co-occurring mutations, which may provide additional clinical value.

Because ALK is rarely expressed at significant levels in normal lung tissue and ALK gene rearrangements lead to ALK overexpression, tests looking for ALK protein can also be clinically useful. Immunohistochemical detection of ALK protein has been shown to reliably detect ALK-positive NSCLCs, and there are currently 2 FDA-approved commercial assays for this use. The convenience and widespread availability of immunohistochemistry (IHC) in most pathology laboratories make IHC an appealing method for detection of ALK in routine care.

Crizotinib

Crizotinib is a potent, orally available, ATP-competitive, small-molecule inhibitor of ALK and Met receptor tyrosine kinases that entered initial clinical trials in 2006 before the discovery of ALK rearrangements in NSCLC. In the initial phase I trial, the ALK-positive cohort had a response rate (RR) of 61%. The most frequently occurring treatment-related adverse events were visual disturbance, gastrointestinal events (nausea, diarrhea, vomiting, and constipation), and peripheral edema. Of note, although visual disturbances were common, occurring in 60% of patients, they were not associated with abnormalities on ophthalmologic examination and did not lead to frequent drug discontinuation.

Subsequently, crizotinib was evaluated in randomized clinical trials in 2 clinical contexts ( Table 1 ). In patients previously treated with platinum doublet chemotherapy, crizotinib was superior to chemotherapy (either pemetrexed or docetaxel), with an improvement in median progression-free survival (PFS) to 7.7 months as compared with 3.0 months for patients receiving chemotherapy. Similarly, crizotinib treatment was associated with an improved RR of 65% compared with only 20% in patients who received chemotherapy. Crizotinib also demonstrated superiority to first-line chemotherapy in a randomized phase III study comparing crizotinib to platinum-pemetrexed as initial therapy. Patients receiving crizotinib had an improved median PFS (10.9 months vs 7.0 months).

Identification of Crizotinib Resistance

Clinically apparent drug resistance occurs after a median of 8 to 11 months of crizotinib treatment through a variety of mechanisms. Broadly, these include alterations of ALK (second-site mutations, alternative splicing, or gene amplification) and reactivation of signaling through alternate pathways. These pattents of resistance stand in contrast to EGFR mutant NSCLC, where resistance to EGFR inhibitors is associated with the EGFR T790M mutation in most patients.

A variety of mutations in the ALK kinase domain have been identified in patients at the time of progression on crizotinib (see Table 3 ). One of the most frequently identified mutations, L1196M substitution, occurs at the conserved gatekeeper site within the kinase domain and is analogous to EGFR T790M mutation. Even mutations at nonactive sites can affect interactions between drug and ALK, as was demonstrated in the case of the C1156Y substitution. Further adding to the complexity, multiple separate secondary mutations have been identified in individual crizotinib-resistant patients demonstrating either tumor heterogeneity or multiple cooperative mutations. Given the diversity of point mutations that occur as resistance mechanisms to ALK inhibition, it will become important to perform repeat biopsyies at the time of progression, potentially yielding information that may help guide further treatment decisions.

In most patients with progression on crizotinib, no ALK-resistance mutations are identified, and therefore, other mechanisms of resistance are likely to be present. One such mechanism is the activation of other pathways such as EGFR and KIT. Although EGFR and ALK mutations are thought to be mutually exclusive, in crizotinib-resistant cell lines, increased EFGR activation due to increased EGFR ligand levels has been demonstrated. Crizotinib resistance caused by amplification of the KIT gene has also been reported, and treatment with imatinib, a small molecule inhibitor of KIT, reversed the resistance phenotype in vitro.

In resistance, changes in ALK copy number (ALK amplification or loss) have been observed in patients, consistent with prior data from cell lines. Although there have also been reports of loss of ALK positivity upon rebiopsy, it remains unclear if this reflects a true loss of an ALK-gene fusion or false negative testing.

Second-Generation Anaplastic Lymphoma Kinase Inhibitors: Ceritinib and Alectinib

Ceritinib is a more potent and specific ALK inhibitor that has demonstrated ability to overcome crizotinib-resistance mutations in vitro. A phase I/II study, including patients who had received crizotinib previously, reported a median PFS of 7.0 months and an RR of 56%. Responses were seen in patients who were found to have a variety of crizotinib-resistance mutations and in patients in whom no resistance mutation was identified. On the basis of this clinical activity in patients with ALK-positive lung cancer who had become resistant to crizotinib, ceritinib received accelerated FDA approval in April 2014.

Similarly, alectinib is a potent and specific ALK inhibitor that has in vitro activity against a variety of ALK mutations that are observed in patients with resistance to crizotinib. After an initial phase I trial in ALK inhibitor–naive patients, investigators conducted global phase I clinical trials that included patients who had progressed or were intolerant to crizotinib, demonstrating an RR of 55%. This RR was confirmed in another phase II study (RR 52%) with patients experiencing a median PFS of 8.1 months. Based on these data, alectinib received an accelerated approval by the FDA in December 2015 for patients resistant to or intolerant of crizotinib. Table 2 summarizes the currently FDA-approved ALK inhibitors and the associated toxicity profiles that have been reported for each agent.

Identification of individual ALK-resistance mutations may have important implications for treatment as these resistance mutations can confer variable sensitivity to second-generation inhibitors. For example, cell lines expressing the I1171T secondary mutation were found to be sensitive to ceritinib but resistant to alectinib, whereas the F1174C mutation appears to confer resistance to ceritinib but sensitivity to alectinib. Notably, the ALK secondary mutation G1202R appears to confer resistance to both ceritinib and alectinib (and therefore all currently FDA-approved ALK inhibitors), representing a particular challenge. Lorlatinib, a newer ALK inhibitor currently in clinical development, may have efficacy in patients with this mutation. The sensitivity of such mutations to currently FDA-approved ALK inhibitors is summarized in Table 3 .

Table 3

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